Article

A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function

  • Nature Structural & Molecular Biology volume 24, pages 419430 (2017)
  • doi:10.1038/nsmb.3389
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Abstract

In the nervous system, rapidly occurring processes such as neuronal transmission and calcium signaling are affected by short-term inhibition of proteasome function. It is unclear how proteasomes are able to acutely regulate such processes, as this action is inconsistent with their canonical role in proteostasis. Here we describe a mammalian nervous-system-specific membrane proteasome complex that directly and rapidly modulates neuronal function by degrading intracellular proteins into extracellular peptides that can stimulate neuronal signaling. This proteasome complex is closely associated with neuronal plasma membranes, exposed to the extracellular space, and catalytically active. Selective inhibition of the membrane proteasome complex by a cell-impermeable proteasome inhibitor blocked the production of extracellular peptides and attenuated neuronal-activity-induced calcium signaling. Moreover, we observed that membrane-proteasome-derived peptides were sufficient to induce neuronal calcium signaling. Our discoveries challenge the prevailing notion that proteasomes function primarily to maintain proteostasis, and highlight a form of neuronal communication that takes place through a membrane proteasome complex.

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Acknowledgements

We thank S.H. Snyder, X. Dong, J. Nathans, G. Seydoux, M. Caterina, C. Machamer, S. Urban, Z. Li, H. Goldschmidt, K. Hopland, C. Vasavda, A. Dietterich, L. Cairns, and members of the Margolis laboratory (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) for reagents and valuable input; R. Huganir (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) for providing anti-NGluR1; and M.E. Greenberg (Harvard Medical School, Boston, Massachusetts, USA) for kindly providing EphB2 antibody. Special thanks to B. Lambrus (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA). This work was funded by institutional funding and the NIH (grant R01 MH102364 to S.S.M.). K.V.R. was supported by the NIGMS (training grant T32 GM007445) and the NSF (Graduate Research Fellowship DGE-1232825).

Author information

Affiliations

  1. Department of Biological Chemistry, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Kapil V Ramachandran
    •  & Seth S Margolis
  2. Solomon H. Snyder Department of Neuroscience, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Seth S Margolis

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Contributions

K.V.R. and S.S.M. designed experiments. K.V.R. performed all experiments. K.V.R. and S.S.M. analyzed and interpreted the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kapil V Ramachandran or Seth S Margolis.

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